Gallium complexes of 3-hydroxy-4-pyrones to treat or prevent hypercalcemia

ABSTRACT

The subjects of this invention are pharmaceutical compositions that comprise gallium complexes of 3-hydroxy-4-pyrones. The compositions have been developed to provide pharmaceutically acceptable gallium bioavailability together with low toxicity, particularly for oral administration. Compositions included in this invention should be useful in providing gallium to humans and other animals for a wide variety of medical and veterinary applications, including the treatment, prevention, or diagnosis of certain bone diseases, certain cancers, and certain disorders of calcium homeostasis.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a divisional of U.S. Ser. No. 08/956,175, filed Oct. 22, 1997,which was a continuation of U.S. Ser. No. 08/655,220, filed Jun. 5,1996, which was a continuation of U.S. Ser. No. 08/505,037, filed Jul.21, 1995, now issued as U.S. Pat. No. 5,574,027, which was acontinuation of U.S. Ser. No. 08/309,624, filed Sep. 21, 1994,abandoned, which was a continuation of U.S. Ser. No. 08/104,623, filedAug. 11, 1993, abandoned, which was a continuation of Ser. No.07/782,434, filed Oct. 25, 1991, now issued as U.S. Pat. No. 5,258,376,which was a continuation-in-part of U.S. Ser. No. 07/656,016, filed Feb.14, 1991, abandoned, which was a continuation of Ser. No. 07/440,277,filed Nov. 22, 1989, abandoned.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to pharmaceutical gallium compositions,particularly those having enhanced oral bioavailability relative tosimple gallium salts and methods for their use. Gallium has demonstratedpharmaceutical value for the treatment of many human and animaldisorders, including hypercalcemia, cancer, and especially certainwidespread degenerative or metabolic bone diseases such as osteoporosisand Paget's disease.

2. References

The following references are cited in this application as superscriptnumbers at the relevant portion of the application:

1. Hart and Adamson, Proceedings of the National Academy of Sciences,U.S.A., 68:1623-1626 (1971)

2. Collery, U.S. Pat. No. 4,596,710

3. Adamson et al., Chemotherapy Reports, 59:599-610 (1975)

4. Warrell, Jr. et al., U.S. Pat. No. 4,529,593

5. Bockman et al., U.S. Pat. No. 4,704,277

6. Warrell, Jr. et al., "Gallium in the Treatment of Hypercalcemia andBone Metastasis", in "Important Advances in Oncology 1989", DeVita, Jr.,Editor, J.P. Lippincott Company, Philadelphia, Pa.

7. Porter, "The Use of Opadry, Coateric, and Surelease in the AqueousFilm Coating of Pharmaceutical Oral Dosage Forms", at pp. 317-362 of"Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms", McGinity,Editor, Marcel Decker, Inc., New York, N.Y. (1989)

8. Nagai et al., "Applications of HPMC and HPMCAS Aqueous Film Coatingsof Pharmaceutical Dosage Forms", at pp. 81-152 of "Aqueous PolymericCoatings for Pharmaceutical Dosage Forms", McGinity, Editor, MarcelDecker, Inc., New York, N.Y. (1989)

9. Jones, "Production of Enteric Coated Capsules", Manufacturing Chemist& Aerosol News, 41:43-57 (1970)

10. Messora, U.S. Pat. No. 3,927,195

11. Porter, "Coating of Pharmaceutical Dosage Forms", at Chapter 91, pp.1633-1643, of "Remington's Pharmaceutical Sciences", Gennaro et al.,Editors, 17th Ed. (1985)

12. Windholz et al., The Merck Index, 9th Edition, pp. 741-742, Merck &Company, Rahway, N.J. (1976)

13. Foster et al., "Gallium Nitrate: The Second Metal With ClinicalActivity", Cancer Treatment Reports, 70:1311-1319 (1986)

14. Hider et al., U.S. Pat. No. 4,575,502

15. Finnegan et al., Inorganic Chemistry, 26:2171-2176 (1987)

16. Farrar et al., Food and Chemical Toxicology, 26:523-525 (1988)

17. Ott, International Journal of Artifical Organs, 6:173-175 (1983)

The disclosures of each of these references are incorporated herein byreference in their entirety.

3. State of the Art

Gallium is known to accumulate in certain tumors, inflamed tissue, andbone tissue by mechanisms that are largely unknown. Binding of galliumto transferrins, particularly lactoferrin, is thought to be responsiblefor some of the transport of gallium in the body, and for theconcentration of gallium in certain tumors and inflamed tissues.Radioactive ⁶⁷ Ga citrate compositions are used in patients to diagnosecertain malignancies and infections, including those in bone tissue.Non-radioactive gallium compositions, and compositions containing otherGroup IIIa elements, have been found effective in treating some tumorsin animals and humans. Gallium is thought to be the most effective ofthese Group IIIa elements¹,3,4. The art recognizes that gallium isuseful for the treatment and prevention of many human and othermammalian diseases, including hypercalcemia, cancer, and certaindegenerative or metabolic bone diseases such as osteoporosis and Paget'sdisease²⁻⁶,13. Gallium itself appears to be the active agent; the formin which the gallium is administered (e.g. as the nitrate, sulfate, orchloride) does not appear to affect its activity to any significantextent³,6.

Gallium is particularly useful in the treatment and prevention ofhypercalcemia and certain bone diseases. Treatable bone diseases includesuch widespread conditions as osteoporosis, osteopenia, Paget's disease,malignant bone disease, bone degeneration due to hyperparathyroidism,and other conditions associated with increased bone resorption orturnover in humans or animals⁴,6. In addition to the above, it has beenfound that gallium increases calcium accretion in bone and decreasesbone resorption⁵.

Specifically, Warrell et al.,⁴,6 and Bockman et al.⁵ disclose treatmentsusing gallium salts, preferably gallium nitrate, for regulating theresorption of calcium from bone in certain bone diseases andhypercalcemia, and for increasing the mass and tensile strength of bone.Warrell et al.⁴ discloses that such regulation entails the generation ofplasma gallium concentrations in the patient of from about 0.9 to 2.0μg/ml whereas Bockman et al.⁵ recite the generation of plasma galliumconcentrations in the patient of from about 0.1 to 5.0 μg/ml.

Treatment of cancer with gallium nitrate is disclosed in Foster et al.¹³which teaches the administration (by infusion) of gallium nitrate at700-750 mg/m² by short infusion every 2-3 weeks; 300 mg/m² /day by shortinfusion for three consecutive days, to be repeated every 2 weeks; and300 mg/m² /day by continuous infusion for 7 consecutive days, to berepeated every 3-5 weeks. Specific cancers treated in this referenceinclude, by way of example, refractory lymphomas, small cell lungcarcinoma, genitourinary malignancies (renal, bladder, prostate,testicular), and multiple myeloma.

On the other hand, Collery² discloses the treatment of cancer by theoral administration of a dose of from 200 mg to 1 gram of galliumchloride per day for at least 2 months.

However, in spite of its established utility, the use of gallium in thetreatment of such diseases is hampered by the fact that ionic galliumlacks high bioavailability when delivered orally. In fact, ionic galliumis a form of gallium which is poorly absorbed by the gastrointestinaltract. In this regard, Warrell et al.⁴ disclose that when a compositionof gallium nitrate is administered orally to a dog, only 0.5 to 2% ofthe gallium is absorbed from the gastrointestinal tract, into thebloodstream and then excreted into the urine. The percent absorption ofother Ga⁻³ salts is not likely to be significantly different, as suchsalts dissociate in aqueous solutions to produce mainly trivalentgallium ions in a similar manner to gallium nitrate.

The low bioavailability of orally delivered gallium salts (i.e., ionicgallium) and the need to generate blood plasma gallium concentrations inthe patient of from 0.1 to 5 μg/ml of plasma gallium concentration (andpreferably 0.5 to 2 μg/ml) for the treatment of hypercalcemia orexcessive bone resorption⁵ requires that either impractically largedoses of orally delivered gallium be administered to the patient or thatthe gallium be administered via non-oral means (e.g., intravenousdelivery). The oral delivery of such gallium salts is not believed to bepractical particularly with widespread, chronic conditions such asosteoporosis and the like.

The present invention is directed to the discovery that galliumbioavailability via oral administration is greatly enhanced by usingelectrostatically neutral gallium chelates of certain3-hydroxy-4-pyrones. The present invention is directed to the furtherdiscoveries that because such neutral gallium chelates decompose in theacidic conditions commonly present in the stomach, pharmaceuticalcompositions of orally delivered neutral gallium chelates must containmeans to inhibit dissociation of the neutral gallium chelates under suchacidic conditions.

In regard to the above, it is noted that Finnegan et al.¹⁵ disclose thepreparation of aluminum and gallium complexes of some3-hydroxy-4-pyrones, including maltol. This reference recites that thealuminum maltol complex is highly neurotoxic when injectedintracranially into rabbits, and suggests further neurotoxicityexperiments with the aluminum and gallium complexes. This referencefurther recites nuclear magnetic resonance spectroscopy (NMR)experiments that demonstrated significant differences between theaqueous behavior of the complexes of aluminum and gallium, i.e.,experiments to determine the stability of gallium complexes as afunction of pH could not be performed, whereas such experiments werereadily performed on aluminum complexes.

Further regarding the significant differences between aluminum andgallium, aluminum is well known in the art to be a cause of degenerativebone disease⁷ as well as being neurotoxic. Contrarily and as previouslydiscussed, gallium is known in the art as effective in the treatment ofdegenerative bone disease and has shown no reported evidence ofneurotoxicity.

Farrar et al.¹⁶ discloses the preparation of an aqueous solutioncontaining 10 mM maltol, 1 mM Ga(NO₃)₃, and a trace of GaCl₃ labelledwith radioactive ⁶⁷ Ga for administration to rats by oral gavage.However, it is not established in this reference that this solutioncontains a significant amount of the neutral 3:1 complex. In any event,Farrar et al. completely fail to even consider the possibility that pHmight affect the stability of a Ga-maltol complex. This reference alsocompletely fails to realize, suggest, or imply any method to increasegallium absorption in fed animals. Additionally, this reference fails tosuggest combining such gallium complexes with means to inhibitdissociation of the complex in a mammalian stomach.

Lastly, Hider et al.¹⁴ disclose orally deliverable pharmaceuticalcompositions containing neutral iron complexes of 3-hydroxy-4-pyronesand means to inhibit dissociation of such complexes under acidicconditions. However, the teachings of this reference are expresslylimited to iron and it is art recognized that gallium is not equivalentto iron. Further in this regard, iron is a Group VIII metal that iseasily oxidized and reduced between its +2 and +3 valences atphysiologic conditions, whereas gallium is a Group IIIa semi-metal thatexists only with a +3 valence state at physiologic conditions.

SUMMARY OF THE INVENTION

In view of the above, the present invention is directed to methods forincreasing the bioavailability of gallium into the bloodstream as wellas to pharmaceutical compositions employed to achieve such methods.

In one of its method aspects, the present invention is directed to amethod for administering gallium to a mammalian patient (e.g., humanpatient) which comprises the oral ingestion of a sufficient amount of apharmaceutical composition comprising

(a) a neutral 3:1 gallium complex of a 3-hydroxy-4-pyrone wherein said3-hydroxy-4-pyrone has the formula ##STR1## wherein each R isindependently selected from the group consisting of hydrogen and alkylof from 1 to 6 carbon atoms; and

(b) means to inhibit dissociation of said complex under acidicconditions of the gastro portion of said gastrointestinal tract

so as to provide a blood plasma gallium concentration of from about 0.1to about 5 μg/ml.

In another method aspect, the present invention is directed to a methodfor increasing calcium accretion in bone or for decreasing calciumresorption in a mammal (e.g., a human), said method comprising orallyadministering an effective amount of a gallium composition to increasecalcium accretion or decrease bone resorption in a mammal in need ofsuch treatment, said gallium composition being a pharmaceuticalcomposition comprising

(a) a neutral 3:1 gallium complex of a 3-hydroxy-4-pyrone wherein said3-hydroxy-4-pyrone has the formula ##STR2## wherein each R isindependently selected from the group consisting of hydrogen, and alkylof from 1 to 6 carbon atoms; and

(b) means to inhibit dissociation of said complex under acidicconditions of the gastro portion of said gastrointestinal tract.

In still another method aspect, the present invention is directed to amethod for administering gallium to a mammalian patient wherein saidadministration is by the oral ingestion of a pharmaceutical compositioncomprising gallium so as to introduce gallium into the gastrointestinaltract of said patient whereupon gallium is absorbed into the bloodstreamof said patient wherein the improvement comprises:

employing in said composition a neutral 3:1 gallium complex of a3-hydroxy-4-pyrone wherein said 3-hydroxy-4-pyrone has the formula:##STR3## wherein each R is selected from the group consisting ofhydrogen, and alkyl of from 1 to 6 carbon atoms; and

further employing in said composition means to inhibit dissociation ofsaid complex under acidic conditions of the gastro portion of saidgastrointestinal tract.

In one of its composition aspects, the present invention is directed toa pharmaceutical composition comprising

(a) a neutral 3:1 gallium complex of a 3-hydroxy-4-pyrone wherein said3-hydroxy-4-pyrone has the formula: ##STR4## wherein each R isindependently selected from the group consisting of hydrogen, and alkylof from 1 to 6 carbon atoms; and

(b) means to inhibit dissociation of said complex under acidicconditions of the gastro portion of said gastrointestinal tract.

The compositions and methods of this invention are useful for orallydelivering gallium to humans and other mammals for a wide variety ofmedical and veterinary applications, including, by way of example, thetreatment of bone diseases relating to the increased resorption ofcalcium into the bloodstream.

DETAILED DESCRIPTION OF THE INVENTION

As noted above, the present invention is directed to methods andcompositions for enhancing the bioavailability of gallium from orallydelivered pharmaceutical compositions containing gallium. However, priorto discussing this invention in further detail, the following terms willfirst be defined. Unless defined below, the terms used herein have theirnormally accepted meanings.

1. Definitions

As used herein, the following terms have the definitions given below:

The term "neutral 3:1 gallium complex of a 3-hydroxy-4-pyrone" refers toan electrostatically neutral complex of Ga⁺³ and 3 equivalents of theanionic form of 3-hydroxy-4-pyrone which complex is represented by theformula [Ga⁺³ (py⁻¹)₃ ] wherein py⁻¹ represents the anionic form of3-hydroxy-4-pyrone which is defined below. Because such complexes do notdissociate to any significant extent in aqueous solutions maintained ata pH of from about 5 to about 9, these complexes remain predominantlyelectrostatically neutral in such solutions.

In this regard, these complexes are deemed "electrostatically neutral"because there are equal numbers of positive and negative charges in thecomplex.

Also, it is apparent that the anionic form of the 3-hydroxy-4-pyroneacts as a chelating agent to the gallium and as such, the complex issometimes referred to herein as "neutral gallium chelates of3-hydroxy-4-pyrones". It being understood that this latter term issynonymous with the term "neutral 3:1 gallium complex of a3-hydroxy-4-pyrone".

The term "a 3-hydroxy-4-pyrone" refers to a compound of the Formula 1:##STR5## wherein from none to three of the hydrogen atoms attached tothe ring carbon atoms are replaced by a hydrocarbon group of from onethrough six carbon atoms.

Specific compounds encompassed by the term "a 3-hydroxy-4-pyrone" arerepresented by the Formulas 2-5 below: ##STR6## wherein each R isindependently a hydrocarbon of from 1 to 6 carbon atoms.

The unsubstituted form of 3-hydroxy-4-pyrone (Formula 2, also calledpyromeconic acid) contains three hydrogen atoms that are bound only toring carbon atoms. As noted above, any combination of these threehydrogen atoms can be substituted with a hydrocarbon group and allpossible combinations of such substitutions are encompassed within thisinvention. The locations of a few possible substitutions are presentedin Formulas 3-5, in which R is a hydrocarbon group (including methyl,ethyl, isopropyl, and n-propyl). The hydrocarbon groups are preferablyacyclic and are preferably unbranched. Groups containing six or fewercarbon atoms, particularly of one through three carbon atoms, especiallymethyl or ethyl, are preferred. Single substitution is preferred; asubstitution at either the 6-position or especially the 2-position ispreferred. Some examples of specific compounds whose gallium complexesmay be used in compositions comprised by the invention are:3-hydroxy-2-methyl-4-pyrone (Formula 3, R=CH₃ --sometimes referred to asmaltol or larixinic acid) and 3-hydroxy-2-ethyl-4-pyrone (Formula 3,R=C₂ H₅ --sometimes referred to as ethyl maltol or ethylpyromeconicacid), both of which are preferred for use in this invention, especially3-hydroxy-2-methyl-4-pyrone. Other preferred compounds include3-hydroxy-4-pyrone (Formula 2--sometimes referred to as pyromeconicacid); and 3-hydroxy-6-methyl-4-pyrone (Formula 4, R=CH₃).

The term "an anion of a 3-hydroxy-4-pyrone" refers to a compound definedin Formulas 2-5 above wherein the hydroxyl proton has been removed so asto provide for the anionically charged form of these compounds.

The terms "oral administration" and "oral ingestion" refer to allconventional forms for the oral delivery of a pharmaceutical compositionto a patient (e.g., human) and that result in the deposition of thepharmaceutical composition into the gastrointestinal tract (includingthe gastro portion of the gastrointestinal tract, i.e., the stomach) ofthe patient. Accordingly, oral administration and oral ingestioninclude, by way of example, actual ingestion of a solid or liquidpharmaceutical composition, oral gavage, and the like.

The term "inhibit dissociation" means that at least 20%, preferably atleast 50% and more preferably at least 80%, of the complex is notdissociated under acidic conditions (e.g., about pH 2-4) for a period ofat least 1 hr and preferably at least 3 hours.

2. Synthesis and Methodology

This invention includes methods for the preparation of neutral 3:1gallium complexes of 3-hydroxy-4-pyrone or 3-hydroxy-4-pyrones whereinfrom one through three of the hydrogen atoms attached to ring carbonatoms are replaced by a hydrocarbon group containing from one throughsix carbon atoms. Such methods comprise reacting such hydroxypyroneswith gallium ions and isolating, at least in part, the resulting complexor complexes.

Specifically, the neutral 3:1 gallium complex of a 3-hydroxy-4-pyrone isprepared by the reaction of gallium ions and the 3-hydroxy-4-pyrones insolution. Gallium ions can be derived from a gallium salt, such as agallium halide, particularly gallium chloride, or a gallium nitratecompound, especially a hydrated gallium nitrate. The gallium nitratecompounds are often preferable as they are easier to work with thangallium halides, which may be highly irritating and may react violentlywith many solvents, including water. Using the proper safeguards, avariety of gallium salts can be used. The reaction is convenientlyeffected in a mutual solvent, including but not limited to mixturescontaining water, ethanol, methanol, and chloroform. Pure water may beused in many cases, though the purification of the gallium hydroxypyronecomplexes may be difficult if it is used. A preferable method, if it isdesired to separate at least a major part of reaction by-products suchas sodium nitrates, sodium chloride, and sodium carbonates, is to use amixture containing roughly equal parts of ethanol and chloroform, with atrace of water. The reaction by-products mentioned above have very lowsolubilities in this mixture and can be removed readily by filtration.

To produce the preferred neutral 3:1 hydroxypyrone:gallium complex, thehydroxypyrone and the gallium ions are mixed in 3:1 molar proportions,preferably with a slight excess of hydroxypyrone to insure a greatpreponderance of the 3:1 complex over the 2:1 and 1:1 complexes. Theproportions of the particular complexes formed are dependent upon the pHof the solution. When a gallium salt such as a halide or nitrate isdissolved, the resulting solution will generally have a low pH. To forma preponderance of the preferred neutral 3:1 complex, a pH of from 5 to9, preferably 7 through 8, is used. If a more acidic solution is used, apreponderance of the less preferred 2:1 and 1:1 complexes may instead beformed, even if a large excess of hydroxypyrone is present. Under highlybasic conditions, poorly soluble gallium hydroxides may precipitate. Itis preferable to regulate the pH with materials other than hydroxidessuch as sodium hydroxide, as the use of such hydroxides may cause theprecipitation of poorly soluble gallium hydroxides, which are notwanted, and the pH may actually be buffered at a low level by thisprecipitation. The use of a carbonate, especially sodium carbonate, ispreferred to regulate the pH. The use of sodium carbonate in a solventmixture containing ethanol and chloroform, for example, can result inthe precipitation of sodium nitrates that are very slightly soluble inthis mixture, and which can be filtered off if desired to help purifythe solution containing the desired pharmaceutical compositions.

The reaction to form the hydroxypyrone-gallium complex in solution isgenerally complete within about five minutes at about 20° C. Gentlestirring or other agitation of the solution promotes a uniform, rapidreaction. Longer reaction times may be used if found necessary.Following the separation, if desired, of reaction by-products such assodium nitrates, sodium chloride, and sodium carbonates (depending onthe solvents and reactants used), the reaction mixture may be evaporatedslowly in air or, more rapidly, through the use of a rotary evaporatoror by freeze drying, as examples. After drying, the gallium complex orcomplexes will remain in solid form. Recrystallization can beaccomplished, if desired, using a suitable solvent, including but notlimited to chloroform, alcohols such as ethanol and methanol, ether,water, acetone, and mixtures containing such solvents. Suitable solventswill depend upon which particular gallium complex(es) and impurities arepresent, upon the impurities to be separated, and upon the temperatureand other physical conditions.

It is noted that the mentioned methods are not the only ones that canproduce hydroxypyrones and gallium complexes with hydroxypyrones andthat various alternative methods may be used as will be apparent tothose skilled in the art. Additionally, in preparing the neutral 3:1complexes of gallium with 3-hydroxy-4-pyrone, a single3-hydroxy-4-pyrone or a mixture of 3-hydroxy-4-pyrones can be used.However, preferably, only a single 3-hydroxy-4-pyrone is employed.

With regard to the preparation of 3-hydroxy-4-pyrones which are used asstarting materials in the preparation of the neutral 3:1 complexes ofgallium with 3-hydroxy-4-pyrones, certain of these compounds occurnaturally and may be obtained by extraction from the natural sources.For example, maltol is found in the bark of the young larch tree (Larixdecidua Mill.), and in pine needles, chicory, wood tars and oils, androasted malt¹². Certain of the 3-hydroxy-4-pyrones are availablecommercially, including maltol and ethyl maltol. Others can be made frompyromeconic acid as a starting material, which can be derived from thedecarboxylation of meconic acid. Methods for preparing such other3-hydroxy-4-pyrones are well known in the art. Additionally, it is notedthat maltol and ethyl maltol are in widespread use as flavoring andfragrance-enhancing agents for foods, and have very low toxicities whentaken orally.

3. Pharmaceutical Compositions

The methods of this invention are achieved by using a pharmaceuticalcomposition comprising a neutral 3:1 complex of gallium with3-hydroxy-4-pyrone and means to inhibit dissociation of said complexunder acidic conditions in the gastro (stomach) portion of thegastrointestinal tract.

As noted above, this invention is directed in part to the discovery thatwhile the neutral 3:1 complex of gallium with 3-hydroxy-4-pyronesdelivers gallium to the bloodstream from the gastrointestinal tract,this complex will dissociate under acidic conditions (generally at a pHof about 4 or less) such as those which can be present in the stomach tothe less absorbable 2:1 and 1:1 complexes, together with freehydroxypyrone and ionic gallium. Accordingly, in order to maintain theorally delivered gallium in a form which is highly absorbable in thegastrointestinal tract, the pharmaceutical compositions of thisinvention are formulated to contain a means to inhibit dissociation ofthis complex when exposed to the acidic conditions of the stomach.

Means to inhibit or prevent dissociation of this complex when exposed tothe acidic conditions of the stomach include the following preferredmethods:

(1) Addition of a sufficient amount of a pharmaceutically compatiblebuffering agent to the 3:1 complex that would bring the pH of thestomach fluids to a range of from about 5-9 and preferably from about6-7 so that the stomach fluids would no longer disrupt the 3:1hydroxypyrone:Ga complex.

Pharmaceutically compatible buffering agents are those which, whileacting as a buffering agent, do not significantly alter the ability ofthe neutral 3:1 gallium complex to deliver gallium to the bloodstream ofthe patient and are not toxic either alone or in combination with theneutral gallium complex. The particular pharmaceutically compatiblebuffering agent employed is not critical. Examples of preferredpharmaceutically compatible buffering agents include, by way of example,calcium carbonate (CaCO₃), sodium bicarbonate (NaHCO₃) and the like. Onthe other hand, aluminum hydroxide, Al(OH)₃, and otheraluminum-containing compounds, by way of example, should be avoided.Other pharmaceutically compatible buffering agents are well known in theart and are reacted in standard pharmaceutical manufacturing textbooks(e.g., Remington's Pharmaceutical Sciences by Mack Publishing Company).

(2) Adding to the pharmaceutical composition containing the 3:1 complexan excess of free hydroxypyrone (or a salt thereof containing aphysiologically acceptable cation), particularly the one used to makethe 3:1 complex. Such a mixture, when dissolved in the stomach, has theeffect of shifting the equilibrium among the 1:1, 2:1, and 3:1 complexestowards a preponderance of the 3:1 complex. In this embodiment, theweight of the free hydroxypyrone incorporated into the formulation ispreferably 0.1 to 100 times the weight of the 3:1 complex employed inthe formulation, and more preferably 0.1 to 10 times. This method, byitself, is not highly preferred but may be used in conjunction withother methods to inhibit dissociation.

(3) Formulating the pharmaceutical composition that contains the 3:1complex in delayed release form, so that a preponderance of the complexis not released until the intestinal tract is reached. An example ofsuch a composition is to formulate the 3:1 complex with certain gels,preferably hydrogels such as a polymerized polyethylene glycol hydrogel,that adsorb the 3:1 complex and then release it after ingestion onlyvery slowly while in the stomach. The preparation of such delayedrelease formulations, particularly those using hydrogels, is well knownin the art.

(4) Most preferably, formulating or packaging the 3:1 complex in such away that the release of the 3:1 complex is prevented or inhibited untilthe basic, or less acidic, conditions of the intestinal tract arereached. Specific preferred methods include:

(a) Encapsulating the 3:1 complex in a material that is resistant todissolution until the intestinal tract is reached, most preferably usinga tablet or capsule that is enteric coated, or granules that are entericcoated, to inhibit or prevent release of the 3:1 complex until a pHgreater than about 5 or 6 is reached. Enteric coating of tablets,capsules, and granules is well known in the art.

(b) Microencapsulating the 3:1 complex within liposomes, preferably madefrom phospholipids, that do not dissociate under the acidic conditionsof the stomach, but that will release the 3:1 complex in the higher pHconditions of the intestinal tract. Such liposomes are also well knownin the art.

The most preferred method, enteric coating tablets, granules orespecially capsules, is well known in the art. Such methods aredescribed, for example, by Porter⁷, by Nagai et al.⁸, by Jones⁹, byMessora¹⁰, and by Porter¹¹, which are incorporated herein by referencein their entirety. Preferred materials for the enteric coating include,by way of example, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, poly(vinyl acetate phthalate), hydroxypropylmethylcellulose acetate succinates, poly(meth)acrylates, and,preferably, cellulose acetate phthalate/diethylphthalate. When capsulesare coated, a plasticizer should be used (such as hydroxypropylmethylcellulose acetate succinates/triethyl citrate or especiallycellulose acetate phthalate/diethylphthalate) to minimize brittleness inthe coating and to inhibit cracking of the coating. Tablets and granulescan also be used.

In addition to the above, two or more means to inhibit dissociation ofthese complexes can be employed in combination so as to enhance thelevel of inhibition, i.e., a pharmaceutically compatible buffer can beemployed in combination with an excess of free 3-hydroxy-4-pyrone.

When used for oral administration, which is preferred, the galliumcomplex may be formulated in a variety of ways. It will preferably be insolid form, and may optionally and conveniently be used in compositionscontaining a pharmaceutically inert carrier including conventional solidcarriers such as lactose, starch, or dextrin, which are convenientlypresented in tablet or capsule form. Materials and methods to enhancegallium absorption, including those mentioned in the precedingparagraph, may be incorporated; the use of enteric coated tablets orcapsules, as previously discussed, is preferred. In this regard, thecomplex itself, with or without additional hydroxypyrone, buffers, orother active ingredients, may also be used without the addition of inertpharmaceutical carriers, particularly for use in capsule form. In thisembodiment, the capsule serves as the means to inhibit dissociation ofthe complex.

Compositions including a liquid pharmaceutically inert carrier (e.g.,water) may also be considered for oral administration that comprise anappropriate means for inhibiting dissociation of the 3:1 complex in theacidic conditions of the stomach, preferably through the use of apharmaceutically compatible buffer, preferably CaCO₃ or NaHCO₃. The useof such buffers is well known in the art.

Doses are selected to provide pharmaceutically active plasma galliumconcentrations for the treatment of excessive resorption of calcium frombone (e.g., arising from hypercalcemia, osteoporosis, osteopenia,Paget's disease or cancer), which are established to be about 0.1-5.0μg/ml, preferably about 0.9-2.0 μg/ml⁴,5. To obtain such physiologicallyactive gallium levels in the patient, compositions for oraladministration provide about 0.1-200 mg/m² /day gallium (delivered as a3:1 complex with hydroxypyrone in the composition) and preferably about1-30 mg/m² /day.

For the 3:1 complexes containing maltol or ethyl maltol, thiscorresponds to a daily dose, preferably given in unit dose form, ofabout 0.9-1800 mg of the complex for a 50 kg individual, preferablyabout 9-360 mg. The compositions, when formulated according to thepreferred methods described above, may be effectively administered atany time, though preferably two or more hours after meals.

The pharmaceutical compositions described herein generally comprise fromabout 1 to about 99 weight percent of a neutral 3:1 complex of galliumwith 3-hydroxy-4-pyrone. Preferably, when an inert pharmaceuticalcarrier is employed in the compositions of this invention, thecompositions contain from about 1 to about 99 weight percent of thepharmaceutically inert carrier. The compositions also contain asufficient amount of a means to inhibit dissociation of the complexunder the acidic conditions of the stomach. Preferably, when such meansinclude a buffer or an excess of hydroxypyrones, the compositioncomprising such means is incorporated into the pharmaceuticalcomposition at no more than about 98 weight percent of the composition.

Formulations may also be considered for other modes of administration,for example per rectum, transdermally, and by intravenous, subcutaneous,and intramuscular injection. These formulations may contain a liquidcarrier that may be oily, aqueous, emulsified, or contain certainsolvents suitable to the mode of administration. Compositions may beformulated in unit dose form, which is preferred, or in multiple orsub-unit doses.

Formulations may also be produced that contain active ingredients otherthan the gallium complexes. These may include other agents to regulatecalcium resorption from bone, for example, but other active agents mayalso be incorporated.

When treating cancer, established doses for gallium nitrate delivery arefrom 300 mg/m² /day to 700 mg/m² /day¹³ which can be extrapolated forthe administration of a 3:1 neutral complex of 3-hydroxy-4-pyrone andgallium.

4. Utility

As noted previously, the art recognizes that gallium is useful intreating conditions such as hypercalcemia, cancer [e.g., refractorylymphomas, small cell lung carcinoma, genitourinary malignancies (renal,bladder, prostate, testicular), multiple myeloma, and the like] anddegenerative bone diseases. For example, the art recognizes that bloodplasma levels of from about 0.1 to about 5 μg/ml are effective intreating hypercalcemia; for treating other degenerative bone diseases;and for increasing the mass and tensile strength of bone⁵.

The compositions and methods of this invention are useful in providingenhanced bioavailability of gallium to the patient's bloodstream ascompared to the bioavailability of gallium achieved with gallium saltcompositions heretofore employed. Accordingly, on equal weight ofgallium basis, pharmaceutical compositions containing a complex of thisinvention together with means to prevent dissociation of the complex inthe patient's stomach deliver significantly greater quantities ofgallium to the bloodstream of a patient as compared to the amount ofgallium delivered to the bloodstream by pharmaceutical compositionscontaining prior art gallium salts. Such enhanced delivery of gallium bypharmaceutical compositions containing neutral 3:1 gallium complexespermit the use of less gallium per unit dose as compared topharmaceutical compositions containing gallium salts while stillproviding efficacious blood plasma gallium concentrations. The use ofless gallium while still achieving the requisite blood plasma galliumconcentrations by the compositions of this invention provides apractical method for the oral delivery of gallium. Additionally, becausethe amount of gallium ingested is reduced, side effects from galliumingestion are expected to be reduced.

Notwithstanding the fact that gallium is administered as a neutralcomplex, the present invention is also based on the discovery thatgallium is nevertheless transported in vivo into the bloodstream of thepatient.

The following examples are offered to illustrate this invention and arenot to be construed in any way as limiting the scope of this invention.

In these examples, the following abbreviations have the followingmeanings:

Å=Angstrom

C=Centigrade

kg=kilogram

M=Molar

mg=milligram

ml=milliliter

mm=millimeter

N=Normal

nm=nanometers

Also, in X-ray fluorescence and diffraction data given in Example 1, thenumbers in parentheses after the value reported represent the estimatedstandard deviation in the last digit.

EXAMPLES Example 1 Preparation of Gallium Ethyl Maltol

A 1.5M solution of ethyl maltol in chloroform is mixed with an equalvolume of a 0.5M solution of gallium nitrate nonohydrate in ethanol toprovide a 3:1 molar ratio of ethyl maltol to gallium ions in themixture. The mixture is stirred for 7 minutes at 22° C. Solid anhydroussodium carbonate is then added in a 10 molar excess, and stirringcontinues for an additional ten minutes. When the sodium carbonate isadded, a trace of water may sometimes need to be added to facilitate thereaction, which is evidenced by some effervescence. The mixture is thenfiltered and the filtrate evaporated to give the solid 3:1 complex ofethyl maltol and gallium.

The complex as so produced contains 14.3(1) weight percent gallium byx-ray fluorescence analysis, as predicted for Ga(C₇ H₆ O₃)₃. Thematerial forms white to pale beige monoclinic crystals with unit cellparameters of about a=7.899(1)Å, b=8.765(1)Å, c=31.626(2)Å,beta=103.253(7) degrees, V=2131 Å³, based on powder x-ray diffractionanalysis. The solubility of this compound is measured as about 5millimolar in distilled deionized water at 23° C. Crystallization fromother solvents or under other conditions may produce other crystalstructures. Under some conditions, water may also be incorporated intothe structure.

Example 2 Bioavailability Study in Rabbits

A test of the oral bioavailability of the 3:1 ethyl maltol:galliumcomplex in rabbits was conducted. In this test, the complex was given torabbits and compared to a solution of gallium nitrate. Six female NewZealand white rabbits weighing between 2.68 and 2.91 kg were used, andwere not fed for 18 hours before starting the experiment. A suspensionof the 3:1 gallium ethyl maltol complex in double distilled water wasprepared with a concentration of 10 mg elemental gallium per 4 ml ofsuspension. A solution of gallium nitrate nonohydrate dissolved indouble distilled water was also prepared, which had a concentration of10 mg elemental gallium per 4 ml of solution. A small amount of solidsodium carbonate was added to the latter solution to bring the pH up toabout 6. Each of the two solutions was given to three rabbits by oralgavage (through a tube inserted through the mouth to the stomach) in theamount of 4 ml per kg of body weight. The stomach tubes were flushed bythree ml of water following administration of the solutions.

Six ml of blood was taken from each rabbit at 1 hour, 2 hours, 4 hours,8 hours, and 24 hours following administration of the solutions, and theserum separated and frozen. Control samples of blood were taken 24 hoursearlier. The frozen serum samples were then sent to an independenttesting laboratory for determination of the gallium contents by graphitefurnace atomic absorption analysis. The testing laboratory receivednumbered serum samples, and never had any knowledge of the experimentalconditions used to produce the samples. The results of the analyses areindicated in Table 1. Due to uncertainties in the analytical proceduresfor gallium in serum, the relative proportions of gallium in the serumsamples are considered more significant than the actual reportedconcentrations.

It is seen from Table 1 that the gallium ethyl maltol suspension wasabsorbed in significantly higher amounts than the gallium nitratesuspension of equal volume and gallium concentration. It is important tonote that no attempt was made to counteract the adverse effects of the3:1 gallium ethyl maltol complex being exposed to the acidic conditionsof the stomach. This study should therefore be considered to give aminimal value for the oral bioavailability of the gallium ethyl maltolcomplex compared to gallium nitrate.

                  TABLE 1                                                         ______________________________________                                        Mean gallium content of rabbit serum (ng/ml).                                            Rabbits treated with                                                          Composition A                                                                          Composition B                                                        (3 animals)                                                                            (3 animals)                                               ______________________________________                                        pre-treatment                                                                              0          0                                                     1 hour       90         51                                                    2 hours      274        99                                                    4 hours      260        118                                                   8 hours      212        103                                                   24 hours     84         64                                                    ______________________________________                                         Composition A = Gallium ethyl maltol suspension                               Composition B = Gallium nitrate solution                                 

Composition A=Gallium ethyl maltol suspension

Composition B=Gallium nitrate solution

Example 3 Preparation of Gallium Maltol

Maltol is dissolved in chloroform to form a 0.75M solution, and galliumnitrate nonohydrate is dissolved in ethanol to form a 0.5M solution. To20 ml of the 0.75M maltol solution in chloroform is slowly added, withcontinuous stirring, 10 ml of the 0.5M gallium nitrate nonohydratesolution in ethanol. The resulting solution is stirred for 5 minutes at23° C. About 5.5 grams of powdered anhydrous sodium carbonate are added,and stirring continues for additional 12 minutes. The mixture isfiltered to remove all solids, and the filtrate is evaporated in arotary evaporator. The remaining crystalline solid is the 3:1maltol:gallium composition. This composition is analyzed using powderx-ray diffraction and found to consist of orthorhombic crystals withunit cell dimensions of about a=18.52(1)Å, b=16.94(1)Å, c=12.02(1)Å. Thesolubility of this composition is measured as about 24 millimolar indistilled deionized water at 23° C.

The stability of the neutral 3:1 maltol:gallium complex was studied inaqueous solutions at various pH values. The complex was studied at twoconcentrations in double distilled deionized water: 2.5×10⁻⁶ M and1.0×10⁻² M. The pH was adjusted by adding either 1N HCl or 1N Na₂ CO₃.The stability of the complex was determined using ultravioletspectroscopy over the region 200-450 nm at 25° C. Several absorptionpeaks are observed in this range, including those at about 212-217 nm,248 nm, 273 nm, 318 nm, and 385 nm. An isobesic point occurs over muchof the pH range at about 290 nm. In the very dilute solutions (2.5×10⁻⁶M), the neutral 3:1 complex appears to be stable from about pH 4.5 to 9.5. For the less dilute solutions (1.0×10⁻² M), the determination wasmore difficult due to the very high absorbance. The stability regionappears very similar to that of the highly dilute solution, possiblyslightly wider.

Example 4 Preparation of Enteric Coated Capsule Formulation

The 3:1 maltol:gallium composition is prepared as described in Example3. Into a standard size 3 hard gelatin capsule (about 15.5 mm long and5.8 mm diameter) is added 40 mg of the 3:1 maltol:gallium composition,10 mg of maltol, and about 190 mg of starch. The capsule is closed andis then coated with a layer of cellulose acetate phthalate/diethylphthalate using a pilot-scale procedure described by Jones⁹. Acetone isused as a solvent, and a coating thickness of about 35 micrometers isobtained. Such a capsule inhibits the release of its contents (the 3:1maltol:gallium composition) in the acidic conditions of the stomach, butreleases its contents in the small intestine, where the pH is greaterthan about 5.5.

Other materials well known in the art can be used to enteric coat thecapsule by merely substituting for the cellulose acetatephthalate/diethyl phthalate employed in Example 4 above. Such othermaterials include, by way of example, cellulose acetate phthalate,hydroxypropyl methylcellulose phthalate, poly(vinyl acetate phthalate),hydroxypropyl methylcellulose acetate succinates, poly(meth)acrylates,and the like.

Example 5 Preparation of Capsules Containing a PharmaceuticallyAcceptable Buffer

The purpose of this example is to demonstrate the preparation of anorally deliverable pharmaceutical composition containing a neutralcomplex of gallium and a 3-hydroxy-4-pyrone wherein the means to inhibitdissociation of the complex in the acidic conditions of the stomach isthe use of a pharmaceutically acceptable buffer. Specifically, 40 mg ofthe 3:1 maltol:gallium composition, from about 50 to about 1000 mg(preferably 500 mg) of calcium carbonate, and the balance starch, areadded to a standard gelatin capsule. The capsule is then closed toprovide a composition of this invention. Such a capsule will inhibit thedissociation of the 3:1 maltol:gallium composition in the acidicconditions of the stomach by raising the pH of the fluid in the stomach.

In view of the above, other neutral complexes of gallium and3-hydroxy-4-pyrones could be prepared in the methods described above bymerely substituting such other 3-hydroxy-4-pyrones for maltol and forethyl maltol described in the above examples. Similarly, other means toprevent dissociation of the neutral complex could be employed by merelysubstituting such other means for the means exemplified above.

Specifically, from about 50 to about 1000 mg of other pharmaceuticallyacceptable buffers can be employed in place of calcium carbonate in thecapsules of Example 5. Such other pharmaceutically acceptably buffersinclude, by way of example, sodium bicarbonate, sodium carbonate and thelike.

What is claimed is:
 1. A method for treating or preventing hypercalcemiain a mammalian individual, comprising;administering a therapeuticallyeffective amount of galium to the individual in the form of a complex ofgallium and a hydroxypyrone, wherein the complex consists essentially ofa neutral 3:1 (hydroxypyrone:gallium) complex in which the hydroxypyroneis either unsubstituted or substituted with one through three loweralkyl substituents which may be the same or different, and wherein thetherapeutically effective amount is such that a blood plasma galliumconcentration is provided that is sufficient to enable treatment orprevention of hypercalcemia.
 2. The method of claim 1, wherein thecomplex is administered in a pharmaceutical composition containing apharmaceutically acceptable carrier.
 3. The method of claim 1, whereinthe blood plasma gallium concentration is in the range of approximately0.1 to 5 μg/ml.
 4. The method of claim 3, wherein the blood plasmagallium concentration is in the range of approximately 0.9 to 2 μg/ml.5. The method of claim 1, wherein the complex is administered orally. 6.The method of claim 2, wherein the carrier is suitable for oraladministration.
 7. The method of claim 6, wherein the carrier is asolid.
 8. The method of claim 7, wherein the pharmaceutical compositionis in the form of a tablet.
 9. The method of claim 7, wherein thepharmaceutical composition is in the form of a capsule.
 10. The methodof claim 6, wherein the carrier is a liquid.
 11. The method of claim 2,wherein the pharmaceutical composition further includes a bufferingagent effective to shift equilibrium towards the neutral 3:1 complexwithin a mixture of gallium hydroxypyrone complexes, including the 1:1,2:1 and 3:1 complexes, which may result when the composition reachesacidic conditions in the stomach of the individual.
 12. The method ofclaim 2, wherein the pharmaceutical composition is encapsulated in amaterial that does not dissolve until the small intestine of theindividual is reached.
 13. The method of claim 2, wherein thepharmaceutical composition is present within a material which decreasesthe rate of release of the complex.
 14. The method of claim 13, whereinthe material is a gel.
 15. The method of claim 1, wherein thehydroxypyrone is selected from the group consisting of3-hydroxy-4-pyrone, 3-hydroxy-2-methyl-4-pyrone,3-hydroxy-2-ethyl-4-pyrone, and 3-hydroxy-6-methyl-4-pyrone.
 16. Themethod of claim 15, wherein the hydroxypyrone is selected from the groupconsisting of 3-hydroxy-2-methyl-4-pyrone and3-hydroxy-2-ethyl-4-pyrone.
 17. The method of claim 16, wherein thehydroxypyrone is 3-hydroxy-2-methyl-4-pyrone.
 18. The method of claim16, wherein the hydroxypyrone is 3-hydroxy-2-ethyl-4-pyrone.
 19. Themethod of claim 2, wherein the pharmaceutical composition furtherincludes an additional active agent.
 20. The method of claim 19, whereinthe additional active agent is effective to regulate calcium resorptionfrom bone.
 21. The method of claim 2, wherein the pharmaceuticalcomposition is in unit dosage form.
 22. The method of claim 2, whereinthe pharmaceutical composition is administered rectally and the carrieris suited to rectal drug administration.
 23. The method of claim 2,wherein the pharmaceutical composition is administered transdermally andthe carrier is suited to transdermal drug administration.
 24. The methodof claim 2, wherein the pharmaceutical composition is administered byintravenous injection and the carrier is suited to intravenous drugadministration.
 25. The method of claim 2, wherein the pharmaceuticalcomposition is administered by subcutaneous injection and the carrier issuited to subcutaneous drug administration.
 26. The method of claim 2,wherein the pharmaceutical composition is administered by intramuscularinjection and the carrier is suited to intramuscular drugadministration.